581675 A7 B7 五、發明說明（I) 本發明係關於以西提里辛(cetirizine)、其各別的光學異 構物或其醫藥上可接受的鹽類來預防氣喘發作的方法。 過去三十年以來氣喘、局部性皮膚炎及花粉熱已盛行 於許多國家(ISAAC.，Lancet 1998:351:1225-32) ’ 且這些疾病 的健康及經濟上的負擔是相當大的。直到目前爲止’並沒 有預防方法顯示可改變氣喘及花粉熱的自然病史。已知在 生命早期暴露於高含量的過敏原是引起氣喘的一種主要原 因（U. WAHN 等，Pediatr. Allergy Immunol. 1997:8(10 suppl):16-20)。在預防過敏原的嘗試已造成相衝突的結果且 完全沒有任何益處（R· S. SEIGER等，Pediatr· Allergy Immunol. 1992:3:110-27)，祇有短暫的效果或在一硏究的案 例中有長期持續效果（U. M· SAARINEN等，Lancet 1995:246:1065-69; D. W. HIDE 等，Allergy:51(2):89-93)。在 局部性皮膚炎及氣喘的後續發展也有極密切關聯，約4 0 %在嬰兒早期患有局部性皮膚炎的嬰兒將在3至4歲的年 齡發展出氣喘。 淸楚地，氣喘的流行及其造成的結果使得對於有效預 防氣喘的方法有所需求。 . 兩種硏究報導酮提芬（ketotifen )在預防具有非專一 j生增加I g E含量的氣喘前(preasthmatic)孩童中氣喘之預 防性使用（Y. likura et al·，Ann. Allergy 1992: 68: 233-36; G. J. 'BUSTOS et al·，Clin. Exp· Allergy 1995: 25(6):568-73)。但是 ，在嬰兒及年幼的孩童中使用酮提芬經常會有關副作用的 情況出現，例如睏倦或精神激動。 3 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀嘴面之注意事項再填寫本頁)581675 A7 B7 V. Description of the Invention (I) The present invention relates to a method for preventing asthma attacks by using citirizine, its respective optical isomers or pharmaceutically acceptable salts thereof. Asthma, local dermatitis, and hay fever have prevailed in many countries over the past three decades (ISAAC., Lancet 1998: 351: 1225-32), and the health and economic burden of these diseases is considerable. So far, there have been no preventative measures that have shown a natural history of altering asthma and hay fever. Exposure to high levels of allergens early in life is known to be a major cause of asthma (U. WAHN et al., Pediatr. Allergy Immunol. 1997: 8 (10 suppl): 16-20). Attempts to prevent allergens have led to conflicting results without any benefits at all (R.S. SEIGER et al., Pediatr. Allergy Immunol. 1992: 3: 110-27) with only transient effects or in a case of intensive research It has long-term sustained effects (U.M. SAARINEN et al., Lancet 1995: 246: 1065-69; DW HIDE et al., Allergy: 51 (2): 89-93). The subsequent development of local dermatitis and asthma is also very closely related. About 40% of infants with local dermatitis in early infancy will develop asthma at the age of 3 to 4 years. Clearly, the prevalence of asthma and its consequences have created a need for effective ways to prevent asthma. Two studies have reported the preventive use of ketotifen in the prevention of preasthmatic children with non-specific asthma that increases I g E content (Y. likura et al., Ann. Allergy 1992: 68: 233-36; GJ 'BUSTOS et al., Clin. Exp · Allergy 1995: 25 (6): 568-73). However, the use of ketotifen in infants and young children often has side effects such as drowsiness or agitation. 3 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on your mouth before filling this page)
--------訂---------線一 經濟部智慧財產局員工消費合作社印製 經濟部智慧財產局員工消費合作社印製 581675 A7 B7 五、發明說明（》 因此，所欲仍在於發現其他治療方法以及預防氣喘發 作，特別是嬰兒及年幼的孩童，之醫藥組成物。 本發明的第一個目的係關於氣喘的主要預防：預防嬰 兒易敏化(sensitisation)而有發展氣喘疾病之危險性。 本發明的第二個目的係在於預防高危險性的嬰兒之過 敏性氣喘，及空氣過敏原（aeroallergen)(禾本科植物花粉或 屋中塵蟎)易敏化的證明。 本發明係基於意料之外的發現，即將包含西提里辛 (cetirizine)、其各別的光學異構物或其醫藥上可接受的鹽類 之醫藥組成物施用至嬰兒中以預防氣喘發作。 本發明係包括一種預防或延遲氣喘發作之方法，其包 含將一治療有效量之西提里辛(cetirizine)、其各別的光學異 構物或其醫藥上接受的鹽類施用於一患者中。 本發明也包括西提里辛(cetirizine)、其各別的光學異構 物或其醫藥上可接受的鹽類之用途，其係用於製備一種欲 用來預防氣喘的藥劑。 本發明也關於欲用來預防患者中氣喘發作的西提里辛 (cetirizine)之用途，該藥劑係在氣喘發作之前施用於該患者 :中（例如在過敏性疾病發生的任何生物或臨床症狀之前（主 要預防)或在對過敏原易敏化的生物徵兆之後但在氣喘症狀 發作之前(次要預防)）。 ^ 本發明也關於用來製備欲用來預防患者中氣喘發作白勺 藥劑之西提里辛(cetirizine)、其各別的光學異構物或其醫藥 上可接受的鹽類之用途，該藥劑係在氣喘發作之前預防性 4 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） J----Ί ----------------訂---------線 (請先閱讀嘴面之注意事項再填寫本頁) 581675-------- Order --------- Line 1 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by 581675 A7 B7 The desire is still to find other treatments and pharmaceutical compositions to prevent the onset of asthma, especially infants and young children. The first object of the present invention is the main prevention of asthma: prevention of infant sensitisation There is a risk of developing asthma. A second object of the present invention is to prevent allergic asthma in high-risk babies, and to easily sensitize aeroallergen (grass plant pollen or house dust mites). The present invention is based on an unexpected discovery that a pharmaceutical composition containing cetizrizine, its respective optical isomers, or a pharmaceutically acceptable salt thereof is administered to an infant for prevention Asthma attack. The present invention includes a method for preventing or delaying an asthma attack, which comprises administering a therapeutically effective amount of cetirizine, its respective optical isomer, or a pharmaceutically acceptable Salts are administered to a patient. The present invention also includes the use of cetizrizine, its respective optical isomers, or its pharmaceutically acceptable salts, which are used to prepare a substance intended for prevention Agents for asthma. The present invention also relates to the use of cetirizine intended to prevent the onset of asthma in a patient which is administered to the patient before the onset of asthma: Either before clinical symptoms (primary prevention) or after biological signs of sensitization to allergens but before the onset of asthma symptoms (secondary prevention). ^ The present invention also relates to the preparation of white blood intended for the prevention of asthma attacks in patients. The use of cetirizine, its respective optical isomers, or its pharmaceutically acceptable salts, which is a spoonful of medicine. This medicine is preventive before the onset of asthma. ) A4 size (210 X 297 mm) J ---- Ί ---------------- Order --------- line (Please read the mouth first (Please fill in this page again)
經濟部智慧財產局員工消費合作社印製 五、發明說明（¾ ) 地施用於該患者中。 本發明也關於用來製備欲用來預防患者中氣喘發作@ 藥劑之西提里辛(cetirizine)、其各別的光學異構物或其醫_ 上可接受的鹽類之用途’該藥劑係用來預防患者易敏化而 有發展爲氣喘疾病之危險性。 在此所使用的西提里辛(cetirizine)—詞係指2-[2-[心(4-氯苯基)苯基甲基]小六氫此哄基]乙氧基]乙酸。製備西提里 辛(cetirizine)、其各別的光學異構物或其醫藥上可接受的鹽 類之方法已敘述於歐洲專利案第0 058 146號、英國專利案 第2.225.320號、英國專利案第2.225.321號、美國專利案 第5,478,941號、歐洲專利案第0 601 028號、歐洲專利案 第0 801 064號以及國際專利案WO 97/37.982中。 在此所使用的“醫藥上可接受的鹽類”一詞係指不僅爲 醫藥可接受非毒性有機及無機酸之加成鹽，例如乙酸、檸 檬酸、順丁烯二酸、琥珀酸、抗壞血酸、氫氯酸、氫溴酸 、硫酸及磷酸以及類似物，亦包括其金屬鹽類(例如鈉或鉀 鹽）或銨鹽、胺鹽及氨基酸鹽類。以西提里辛(cetirizine)二 氫氯化物以得到最佳的結果。 ; 在此使用之“各別的光學異構物”一詞係代表西提里辛 (cetirizine)的右旋及左旋對掌異構物。更精確而言，其表示 • 活性物質包含至少9 0重量％，較佳爲至少9 5重量％之 <西提里辛(cetirizine)—個各別的光學異構物，以及至少1 〇 重量％，較佳爲至少5重量％之西提里辛(cetirizine)的其他 各別光學異構物。每一個各別的光學異構物可以習知方法 5 ΙΊ ijlilm — ·1111111 ^« — — — — 1 —-- (請先閲讀*f面之注意事頊存填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 581675 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（f) 得到，即由相對的消旋混合物之解析或由非對稱性合成而 得。 患者一詞，可瞭解爲嬰兒及孩童’特別是年幼的孩童 ，一般而言，患者係爲3個月至1 0歲年齡的嬰兒或孩童 ，較佳爲6個月至5歲’且更佳爲10個月至5歲者。患 者年齡在1至4歲可得到吹好的結果。 根據本發明，患者未受到氣喘疾病的影響，較佳地， 患者從未受到氣喘疾病的影響。 氣喘係爲一種發炎疾病，症狀爲出現咳嗽及/或發出 氣喘聲，特別是週期性的咳嗽及/或氣喘聲，且更特別的 是過敏性的氣喘聲或夜間咳嗽，並有睡眠干擾持續至少連 續2晚。氣喘可定義於至少2個夜間咳嗽的分別事件及睡 眠千擾持續2晚或任何需要治療之發出氣喘聲的事件；發 出氣喘聲或夜間咳嗽的第二個事件係被認爲是第一次氣喘 的侵襲。 一種治療上有效量的西提里辛(cetirizine)、其各別的光 學異構物或其醫藥上可接受的鹽類係用來減緩氣喘侵襲的 影響或者預防或延遲氣喘侵襲的開始。劑量主要係視施用 :的特定方法及預防的目的而定，各別的劑量大小及施用的 « 畫可基於相關情況的各別分析而決定。需要決定相關因 素之方法爲熟習此技術的專家所熟知。 < 一較佳的每日劑量係提供每個患者每公斤體重約 0.0005毫克至約2毫克的西提里辛(cetirizine)、其各別的光 學異構物或其醫藥上可接受的鹽類。一特別較佳的每曰劑 6 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） Ί I Γ — ------· I I----—訂·- —-----線 (請先閱讀贵面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 581675 A7 _______ B7 五、發明說明（s) 量係爲每個患者每公斤體重約0.005至約2毫克。最佳的 結果是由以每個患者每公斤體重約0.05至1毫克的每日劑 量而得到。此劑量可由每日治療施用一次，或分成較小的 劑量，例如每天1至4次，且較佳爲每天1至3次，並施 用超過約2 4小時的時間以達到一全部給予的劑量。最佳 的結果是以每天施用兩次而得到；本發明的醫藥組成物係 以每天相等的劑量來施用。其中組成物被施用之實際劑量 可根據使用的類型、使用的模式、患者的需求由熟習此技 術者所決定而有不同，對患者的實際劑量可特定地由熟習 此技術者根據狀況的嚴重性、所使用的特殊配方以及其他 可能涉及的其他藥物而改良。 根據本發明所使用的醫藥組成物可由任何習知方法所 施用。施用的途徑包括皮下、經皮、緩釋施用、肌肉下、 口服及鼻內途徑。可使用任何其他習知施用的途徑，例如 經由上表皮或黏膜皮膚內層而吸收。 根據本發明的醫藥形式可以藥劑師所使用的習知方法 來製備。該等形式可與其他成份或生物學上的活性劑、醫 藥上可接受的界面活性劑、賦形劑、載劑、稀釋劑及媒液 :共同施用。 \： ~本發明的醫藥組成物包括任何習知的治療之惰性載劑 ，該等醫藥組成物可包括惰性以及藥物動力學上具活性的 •添加物。液態組成物舉例而言可採用與水可溶混的無菌溶 液之形式。此外，習用作爲保存、穩定、保持濕度及乳化 劑之物質以及例如改變滲透壓的物質、改變pH値如緩衝 7 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1— 訂·！I 線· (請先閱讀嘴面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 581675 A7 __B7 五、發明說明（G) 液的物質、以及其中添加物也可存在。若有需要，抗氧化 劑也可包括於醫藥組成物中。對組成物而言，醫藥可接受 的賦形劑或載劑包括鹽水、緩衝的鹽水、右旋糖或水。組 成物也可包含特定的穩定劑，例如糖，包括甘露糖及甘露 醇。載劑物質及稀釋劑可爲有機或無機物質，例如水、明 膠、乳糖、澱粉、硬脂酸鎂、滑石、阿拉伯膠、聚亞烷基 乙二醇及其類似物。必要條件係爲用於製造醫藥組成物中 所有的佐劑及物質爲不具毒性的。 醫藥組成物可以噴霧吸入來施用。可使用任何用於噴 霧吸入施用的習知醫藥組成物。另一個較佳的施用模式係 藉由氣溶膠方式進行。 本發明的醫藥組成物也可製成配方以用於局部施用。 用於局部施用的組成物可以水溶液、洗劑或膠狀物、油性 溶液或懸浮液或是脂肪或乳化油膏的形式存在。 本發明的醫藥組成物也可用於以聚合物基質中經皮治 療系統之緩慢延長的釋放或以適合的配方用於口服緩釋上 〇 根據本發明的醫藥組成物也可以口服或經直腸地施用 :。其等也可以經鼻滴注（氣溶膠)或以軟膏或乳霜形式存在 可用於口服施用的醫藥組成物可爲固態或液態，例如， 以未塗覆或塗覆的錠片、藥片、裹糖衣的藥九(dragee)、明 <膠膠囊、溶液、糖漿及類似物之形式。就經直腸途徑之施 用而言，含有本發明化合物的組成物一般係以栓劑形式使 用。 8 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -J---Ί ----------------訂---------線 (請先閱讀嘴面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 581675 A7 B7 五、發明說明（7) 醫藥形式，例如錠片、滴劑、栓劑及類似者，係由習 知的醫藥方法製備。本發明的化合物係與固態或液態、不 具毒性且醫藥上可接受的載劑混合，且可能與一分散劑、 裂解劑(disintegration agent)、穩定劑及類似物混合。若適合 時，也可加入防腐劑、增甜劑、著色劑及類似物。 較佳地，本發明的醫藥組成物係以口服用藥之傳統形 式來施用，如薄膜塗覆的錠片、錠劑、裹糖衣的藥九，以 及口服液態製劑例如糖漿。 最佳的結果係以口服劑量形式，特別是液態配方例如 糖漿而獲得。舉例而言，患者每日可接受1 〇毫克/毫升 西提里辛(cetirizine)口服溶液0 · 25毫克/公斤之兩個劑 量（每日總劑量：0 · 5 0毫克/公斤/天）；一毫升的 該溶液包括2 0滴，且每一滴西提里辛(cetidzine)包括0 · 5毫克。 根據本發明的組成物之實施例，下列糖漿的配方爲較 佳的：西提里辛(cetirizine)二氫氯化物，硬脂酸鎂，纖維素 ，乳糖以及二氧化矽。 本發明的醫藥組成物在預防上爲有效的。這些組成物1 ，可減輕氣喘侵襲的影響，這些組成物可延遲或預防氣喘的 作。 本發明的醫藥組成物使得類皮質激素（corticoid)化合 •物(例如皮質類固醇）需要用於任何氣喘疾病上之需求降@ 〇 本發明的另一個優點在於此方法預防氣喘侵襲的發作 9 _____ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 丨·— 丨:丨 T!丨！ 訂-! — — — 線 (請先閱讀背面之注意事項再填寫本頁) 581675 A7 B7 五、發明說明（7) (atopic)皮膚炎的年幼兒童氣喘之發作（當與安慰劑比較時） 。也預知基於生物標記的基線狀態之次族群以及特定的患 者(亦即僅發出喘氣聲者；氣喘發作日期爲包含該症狀後至 少3個月）。氣喘發生降低3 0%被認爲係爲臨床上相關的 。其功效的第二個因素包括氣喘的嚴重性以及特異反應性 皮膚炎。以西提里辛(cetirizine)二氫氯化物對嬰兒之長效治 療也已被評估。 此實施例的目標族群係由年齡爲1至2歲之登記前具 有特異反應性皮膚炎活性症狀至少一個月的嬰兒。所有的· 嬰兒必須有至少一個雙親或兄弟姊妹具有特異反應性疾病（ 特異反應性皮膚炎、過敏性鼻炎或氣喘)的歷史，除外的是 具有氣喘、或具有發出氣喘聲或夜間咳嗽的任何事件歷史 之嬰兒以及可能模糊氣喘的診斷之任何狀況(Guidelines for the diagnosis and management of asthma. National Asthma Education and Prevention Program. Expert Panel Report. International consensus report on diagnosis and treatment of asthma. National Heart, Lung and Blood Institute. National Institute of Health publication 92-3091) o ； 此試驗係爲以西提里辛(cetirizine)二氫氯化物進行前瞻 \性的、隨機的、雙盲的、相等族群(parallel group)以及以安 慰劑作爲控制組之試驗。 < 特異反應性皮膚炎之嚴重性係以特異反應性皮膚炎等 級 SC0RAD 來分級（Consensus Report of the European Task Force on Atopic Dermatitis. Severity Scoring of Atopic 11 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） j ----:丨-----------------訂---------線 (請先閱讀贵面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 581675 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（// ) 試驗劑量爲0 · 2 5毫克西提里辛(cetirizine)/公斤b.i.d. (b.i.d.= "bis in die”，每天兩次）。 樣品大小係基於在1 8個月治療後安慰劑組4 Ο %的 兒童之預期氣喘累計發生率而定。發生率降低3 0 %被認 爲是臨床上相關的。 兩個治療組之基線特性，包括平均SCORAD値、特異 反應性(atopy)家族史及環境因子，係爲可比較的。 具有提高基線含量的血淸全部I g E 03 0 k U / 1 )或專一性 I g E 抗體 U0.35 kUA/1) 之安慰劑組兒童係有增加相對之發展氣喘的危險性(表1 ) 。在所有測定的I g E抗體係觀察到此種增加，且在全部 I g E、禾本科植物花粉、家居塵蟎及貓發怒過敏原上極 明顯。 本發明試驗首先係在於顯示對這類年幼嬰兒的易敏感 性是未來氣喘發作的有力預測。 基於免疫參數之次族群分析顯示高臨床相關性之統計 學上顯著的差異性(表2 -圖1及2 )。 以提高基線含量之全部IgEU30 k U/ 1 ) :或專一性IgE抗體U0.35 kUA/Ι)開始此試 ^驗；接受西提里辛(cetirizine)二氫氯化物的嬰兒，與那些接 受安慰劑之具提高基線I g E抗體的嬰兒相比較，係具有 '降低之發展氣喘的危險性。 在所有測定的I g E抗體係觀察到此種降低，且在禾 本木植物花粉（p = 〇 · 〇 〇 2 )及家居塵蟎（P = 0 · ____ 13___ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱1 ------Γ — ^----------------訂---------線 (請先閱讀贵面之注意事項再填寫本頁) 581675 A7 五、發明說明（0) 高度成本有效性。 在嬰兒的大型試驗已顯示西提里辛(cetirizine)二氫氯化 物係爲一種安全的產品。使用西提里辛{cetirizine}二氫氯化 物於具有特異反應性皮膚炎的嬰兒上之雙盲試驗顯： 成功地預防證明對禾本科植物花粉或家居塵蟎易敏感 嬰兒之氣喘。 ^ 表1 :以基線異位特性安慰劑ITT族群（η = 3 氣喘發生率 性的 ? 正常增加在增加標記物的存在下發 (%) (%) 展氣喘的RR '及 [95% CI] 經濟部智慧財產局員工消費合作社印製 全部的 I g E (PRIST)* (33.5) (43.6) 1.3 [1.0; 1.7] I g E禾本科植物花粉 (GXI)* (35.0) (58.8) 1.7 [1.2; 2.3] I g E HDM(Dl)* (34.7) (51.5) 1.5 [1.1 ; 2.0] I g E貓發怒(El)* (33.2) (47.1) 1.4 [1.0; 1.9] I g E 蛋（FI)* (30.7) (39.3) 1.3 [0.9; 1.8] :^迟牛奶阳)* (36.0) (40.9) 1.1 [0.9; 1.5] I g E HDM+禾本科植 物花粉 (32.9) (53.7) 1.6 [1.2; 2.1] 嗜伊紅血球計數 (34.9) (47.6) 1.4 [1.0; 1.9]Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. The invention description (¾) was applied to this patient. The present invention also relates to the use for the preparation of asthma attacks that are to be used in patients @ 药 的 西蒂里辛 (cetirizine), their respective optical isomers or their pharmaceutically acceptable salts It is used to prevent patients from being susceptible to susceptibility to developing asthma. Cetirizine as used herein—the word refers to 2- [2- [心 (4-chlorophenyl) phenylmethyl] 小 hexahydro this couryl] ethoxy] acetic acid. Methods for the preparation of cetirizine, its respective optical isomers or their pharmaceutically acceptable salts have been described in European Patent No. 0 058 146, British Patent No. 2.225.320, United Kingdom Patent No. 2.225.321, US Patent No. 5,478,941, European Patent No. 0 601 028, European Patent No. 0 801 064, and International Patent No. WO 97 / 37.982. The term "pharmaceutically acceptable salts" as used herein refers to addition salts that are not only pharmaceutically acceptable non-toxic organic and inorganic acids, such as acetic acid, citric acid, maleic acid, succinic acid, ascorbic acid , Hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and the like, and also include metal salts (such as sodium or potassium salts) or ammonium salts, amine salts and amino acid salts. For best results, use citirizine dihydrochloride. The term "individual optical isomers" as used herein means the right-handed and left-handed isomers of cetizrizine. More precisely, it means that the active substance contains at least 90% by weight, preferably at least 95% by weight, < cetirizine, a separate optical isomer, and at least 10% by weight %, Preferably at least 5% by weight of other individual optical isomers of cetirizine. For each individual optical isomer, you can learn the method 5 ΙΊ ijlilm — · 1111111 ^ «— — — — 1 —-- (Please read the notes on the * f side first, fill out this page) This paper is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 581675 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (f), that is, the analysis of the relative racemic mixture or the asymmetry Synthesized. The term patient can be understood as infants and children ', especially young children. Generally speaking, patients are infants or children aged 3 months to 10 years, preferably 6 months to 5 years' and more Preferably from 10 months to 5 years. Patients aged 1 to 4 years can get good results. According to the present invention, the patient is not affected by the asthma disease, and preferably, the patient is never affected by the asthma disease. Asthma is an inflammatory disease with symptoms of coughing and / or wheezing, especially periodic coughing and / or wheezing, and more particularly allergic wheezing or nighttime coughing, and sleep disturbances that persist for at least 2 consecutive nights. Asthma can be defined as at least 2 separate events of nocturnal cough and sleep disturbances lasting 2 nights or any event requiring asthma that requires treatment; the second event of asthma or nocturnal cough is considered to be the first asthma Invasion. A therapeutically effective amount of cetirizine, its respective optical isomer, or a pharmaceutically acceptable salt thereof is used to reduce the effects of asthma attacks or prevent or delay the onset of asthma attacks. The dose depends mainly on the specific method of administration and the purpose of prevention. The size of each dose and the application «can be determined based on individual analysis of the situation. Methods that need to determine the relevant factors are well known to experts skilled in this technology. < A preferred daily dose is to provide from about 0.0005 mg to about 2 mg of cetirizine, its respective optical isomer, or a pharmaceutically acceptable salt thereof per kg of body weight per patient. . A particularly preferred paper size of 6 is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) Ί I Γ — ------ · I I ----— Order ·-— ----- Line (Please read the precautions for your face before filling out this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 581675 A7 _______ B7 V. Description of the invention (s) The amount is per kilogram of body weight per patient About 0.005 to about 2 mg. The best results are obtained with a daily dose of about 0.05 to 1 mg per kilogram of body weight per patient. This dose may be administered once daily for treatment, or divided into smaller doses, such as 1 to 4 times per day, and preferably 1 to 3 times per day, and administered over a period of about 24 hours to achieve a fully administered dose. The best results are obtained by administering twice a day; the pharmaceutical composition of the present invention is administered at an equivalent daily dose. The actual dose to which the composition is administered may vary depending on the type of use, the mode of use, and the needs of the patient, as determined by those skilled in the art. The actual dose to the patient may be specifically determined by the person skilled in the art according to the severity of the situation. , Special formulas used, and other drugs that may be involved. The pharmaceutical composition used according to the present invention can be administered by any conventional method. Routes of administration include subcutaneous, transdermal, sustained release, submuscular, oral and intranasal routes. Any other conventional route of administration can be used, such as absorption through the epidermis or the inner layer of the mucosal skin. The medicinal form according to the present invention can be prepared by a conventional method used by a pharmacist. These forms can be co-administered with other ingredients or biologically active agents, pharmaceutically acceptable surfactants, excipients, carriers, diluents and vehicles. \: ~ The pharmaceutical composition of the present invention includes any conventional therapeutic inert carrier. Such pharmaceutical compositions may include inert and pharmacokinetically active additives. The liquid composition may, for example, take the form of a water-miscible sterile solution. In addition, it is used as a substance for storage, stability, humidity and emulsifiers, as well as substances that change osmotic pressure, such as changing the pH, such as buffering. 7 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 1— Order! Line I (Please read the notes on the mouth first and then fill out this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 581675 A7 __B7 V. Description of the invention (G) The substance of the liquid and its additives may also be present. If necessary, antioxidants may also be included in the pharmaceutical composition. For the composition, pharmaceutically acceptable excipients or carriers include saline, buffered saline, dextrose or water. The composition may also contain specific stabilizers, such as sugars, including mannose and mannitol. Carrier materials and diluents can be organic or inorganic materials such as water, gelatin, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycol, and the like. The necessary condition is that all adjuvants and substances used in the manufacture of pharmaceutical compositions are non-toxic. The pharmaceutical composition can be administered by spray inhalation. Any conventional pharmaceutical composition for aerosol administration can be used. Another preferred mode of application is by aerosol. The pharmaceutical composition of the present invention can also be formulated for topical application. Compositions for topical application can be in the form of aqueous solutions, lotions or gels, oily solutions or suspensions, or fats or emulsified ointments. The pharmaceutical composition of the present invention can also be used for slow extended release of a transdermal therapeutic system in a polymer matrix or for oral sustained release in a suitable formulation. The pharmaceutical composition according to the present invention can also be administered orally or rectally. :. They may also be administered nasally (aerosol) or in the form of an ointment or cream. Pharmaceutical compositions useful for oral administration may be solid or liquid, for example, as uncoated or coated tablets, tablets, wrap Sugar-coated forms of dragee, Ming < gel capsule, solution, syrup and the like. For transrectal administration, compositions containing a compound of the invention are generally used in the form of suppositories. 8 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -J --- Ί ---------------- Order ------- --Line (please read the notes on the mouth first and then fill out this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 581675 A7 B7 V. Description of the invention (7) Pharmaceutical forms, such as tablets, drops, suppositories and the like Or, it is prepared by a known medical method. The compound of the present invention is mixed with a solid or liquid, non-toxic and pharmaceutically acceptable carrier, and may be mixed with a dispersant, a disintegration agent, a stabilizer and the like. Where appropriate, preservatives, sweeteners, colorants and the like may also be added. Preferably, the pharmaceutical composition of the present invention is administered in a conventional form for oral administration, such as film-coated tablets, lozenges, sugar-coated tablets, and oral liquid preparations such as syrup. The best results are obtained in oral dosage form, especially in liquid formulations such as syrups. For example, patients may receive two daily doses of 10 mg / ml cetirizine oral solution 0.25 mg / kg (total daily dose: 0.5 mg / kg / day); One milliliter of this solution includes 20 drops, and each drop of cetidzine includes 0.5 mg. According to an embodiment of the composition of the present invention, the following syrup formulations are preferred: Cetirizine dihydrochloride, magnesium stearate, cellulose, lactose, and silicon dioxide. The pharmaceutical composition of the present invention is effective for prevention. These compositions 1 can reduce the effect of asthma attacks, and these compositions can delay or prevent the action of asthma. The medicinal composition of the present invention reduces the need for corticoid compounds (such as corticosteroids) for any asthma disease @ 〇 Another advantage of the present invention is that this method prevents the onset of asthma attacks 9 _____ This Paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 丨 · — 丨: 丨 T! 丨! Order-! — — — Thread (please read the notes on the back before filling this page) 581675 A7 B7 V. Description of the Invention (7) (atopic) Asthma attack in young children with dermatitis (when compared with placebo) . Subgroups based on biomarker-based baseline status and specific patients are also foreseen (i.e., those who only produce wheezing; the asthma attack date is at least 3 months after including the symptom). A 30% reduction in asthma is considered clinically relevant. A second factor in its efficacy includes the severity of asthma and atopic dermatitis. The long-term effects of cetirizine dihydrochloride on infants have also been evaluated. The target ethnic group in this example is infants who have symptoms of atopic dermatitis activity for at least one month before registration at the age of 1 to 2 years. All infants must have at least one parent or sibling with a history of atopic disease (atopic dermatitis, allergic rhinitis, or asthma), with the exception of any event that has asthma, or has had an asthma sound or nocturnal cough History of infants and any condition that may obscure the diagnosis of asthma (Guidelines for the diagnosis and management of asthma. National Asthma Education and Prevention Program. Expert Panel Report. International consensus report on diagnosis and treatment of asthma. National Heart, Lung and Blood Institute National Institute of Health publication 92-3091) o; This trial was prospective, randomized, double-blind, parallel group and placebo with cetizrizine dihydrochloride As a control group test. < The severity of atopic dermatitis is graded according to the level of atopic dermatitis SC0RAD (Consensus Report of the European Task Force on Atopic Dermatitis. Severity Scoring of Atopic 11) This paper standard applies to China National Standard (CNS) A4 (210 x 297 mm) j ----: 丨 ----------------- Order --------- line (please read the note of your face first) Please fill in this page again) Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs's Consumer Cooperatives 581675 Printed by the Intellectual Property Bureau of the Ministry of Economics's Consumer Cooperatives A7 B7 V. Description of the Invention (//) The test dose is 0 · 25 mg Citilinine ( cetirizine) / kg bid (bid = " bis in die "twice daily). Sample size is based on the expected cumulative incidence of asthma in 4 0% of children in the placebo group after 18 months of treatment. Incidence A reduction of 30% was considered clinically relevant. The baseline characteristics of the two treatment groups, including mean SCORAD (R), family history of specific reactivity (atopy), and environmental factors, were comparable. Blood with increased baseline content淸 All I g E 03 0 k U / 1) or specific I g E resistance U0.35 kUA / 1) children in the placebo group had an increased relative risk of developing asthma (Table 1). This increase was observed in all tested I g E resistance systems, and in all I g E, Wo The pollen, house dust mite, and cat irritated allergens are very obvious in the undergraduate plants. The test of the present invention is firstly to show that the susceptibility to this kind of young infants is a powerful prediction of future asthma attacks. Subgroup analysis based on immune parameters shows high Statistically significant differences in clinical relevance (Tables 2-Figures 1 and 2). Start the trial with an increase in baseline IgEU30 k U / 1): or specific IgE antibody U0.35 kUA / 1) Test; infants receiving cetirizine dihydrochloride had a 'reduced risk of developing asthma compared to infants receiving placebo with increased baseline Ig E antibodies. In all assays This reduction was observed with the I g E resistance system, and was found in grass pollen (p = 〇 · 〇〇2) and house dust mites (P = 0 · ____ 13___). This paper is sized to the Chinese National Standard (CNS) A4. (210 X 297 Public Love 1 ------ Γ-^ ------------- --- Order --------- line (please read the precautions of your noodles before filling out this page) 581675 A7 V. Description of the invention (0) High cost effectiveness. Large trials in infants have shown that the cetizine dihydrochloride system is a safe product. A double-blind test using cetirizine dihydrochloride on infants with atopic dermatitis showed successful prevention of asthma in babies who were susceptible to susceptibility to grass pollen or house dust mites. ^ Table 1: Placebo ITT population with baseline ectopic characteristics (η = 3 Asthma incidence? Normal increase in the presence of increased markers (%) (%) RR for asthma and [95% CI] All I g E (PRIST) * (33.5) (43.6) 1.3 [1.0; 1.7] I g E grass pollen (GXI) * (35.0) (58.8) 1.7 [ 1.2; 2.3] I g E HDM (Dl) * (34.7) (51.5) 1.5 [1.1; 2.0] I g E Cat anger (El) * (33.2) (47.1) 1.4 [1.0; 1.9] I g E egg ( FI) * (30.7) (39.3) 1.3 [0.9; 1.8]: ^ Late Milk Sun) * (36.0) (40.9) 1.1 [0.9; 1.5] I g E HDM + Gramineous plant pollen (32.9) (53.7) 1.6 [ 1.2; 2.1] Eosinophil count (34.9) (47.6) 1.4 [1.0; 1.9]
Pft '0·〇〇1 0·〇〇5 0.〇32 0*lS2 °·25〇 '0·〇〇1 〇·〇6§ /^$先閱讀脅面之注意事項再填寫本頁) 15 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公爱）Pft '0 · 〇〇1 0 · 〇〇5 0.〇32 0 * 1S2 ° · 25〇'0 · 〇〇1 〇 · 〇6§ / ^ $ Read the precautions before filling in this page) 15 This paper size applies to China National Standard (CNS) A4 (210 χ 297 public love)
581675 A7 五、發明說明（4) 經濟部智慧財產局員工消費合作社印製 ITT 意欲治療 RR 相對危險性 CI 可信賴區間(confidence interval) ()* Pharmacia & Upjohn Diagnostics references HDM 家居塵蟎 增加値 全部 I g E : 230 kU/1， 專一性 I g E :⑽35kUA/l， 嗜伊紅血球：20.7giga/l 表2 :於ITT族群中治療之氣喘發生率 安慰劑西提里辛 在以西提里辛 (%) (cetirizine) (cetirizine)治療時發展 (%) 氣喘的RR [95% CI] 對數等級 試驗 P値 ITT族群 (38.0) (37.7) [0.8; 1.2] 0.973 在基線時具有增加的I g E或嗜伊紅血球之次族群 全部的 I g E (PRIST)* (43.6) (38.1) 0.9 [0.7; 1.1] 0.391 I g E禾本科植物花粉 (GXI)* (58.8) (27.8) 0.5 [0.3 ; 0.9] 0.002 I g E HDM(Dl)* (51.5) (28.6) 0.6 [0.3 ; 0.9] 0.005 I g E貓發怒(El)* (47.1) (40.6) 0.9 [0.6; 1.3] 0.610 ·: 、I g E 蛋(FI)* (39.3) (31.2) 0.8 [0.6; 1.1] 0.292 I g E 牛奶（F2)* (40.9) (30.7) 0.7 [0.5 ; 1.0] 0.140 I g E HDM+禾本科植 物花粉 (53.7) (34.2) 0.6 [0.4; 0.9] 0.006 嗜伊紅血球計數 (47.6) (42.7) 0.9 『0.6; 1.31 0.674 16 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） (請先閱讀嘴面之注意事項再填寫本頁)581675 A7 V. Description of the invention (4) ITT printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs intends to treat RR Relative risk CI confidence interval () * Pharmacia & Upjohn Diagnostics references HDM Household dust mite increase 値 All I g E: 230 kU / 1, specificity I g E: ⑽35 kUA / l, eosinophils: 20.7 giga / l Table 2: The incidence of asthma treated in the ITT population (%) (cetirizine) (cetirizine) Development during treatment (%) RR of asthma [95% CI] Log-rank trial P 値 ITT population (38.0) (37.7) [0.8; 1.2] 0.973 Has an increased I g at baseline E or all subgroups of eosinophils I g E (PRIST) * (43.6) (38.1) 0.9 [0.7; 1.1] 0.391 I g E pollen (GXI) * (58.8) (27.8) 0.5 [0.3 ; 0.9] 0.002 I g E HDM (Dl) * (51.5) (28.6) 0.6 [0.3; 0.9] 0.005 I g E Cat Rage (El) * (47.1) (40.6) 0.9 [0.6; 1.3] 0.610 ·:,, I g E Egg (FI) * (39.3) (31.2) 0.8 [0.6; 1.1] 0.292 I g E Milk (F2) * (40.9) (30.7) 0.7 [0.5; 1.0] 0.140 I g E HDM + Gramineae Pollen (53.7) (34.2) 0.6 [0.4; 0.9] 0.006 Eosinophil count (47.6) (42.7) 0.9 『0.6; 1.31 0.674 16 This paper size applies to China National Standard (CNS) A4 (210 X 297 public love) (Please read the precautions before filling in this page)